Cargando…

Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective...

Descripción completa

Detalles Bibliográficos
Autores principales: Mizuno, Yu, Yamamotoya, Takeshi, Nakatsu, Yusuke, Ueda, Koji, Matsunaga, Yasuka, Inoue, Masa-Ki, Sakoda, Hideyuki, Fujishiro, Midori, Ono, Hiraku, Kikuchi, Takako, Takahashi, Masahiro, Morii, Kenichi, Sasaki, Kensuke, Masaki, Takao, Asano, Tomoichiro, Kushiyama, Akifumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801943/
https://www.ncbi.nlm.nih.gov/pubmed/31546603
http://dx.doi.org/10.3390/ijms20194680
_version_ 1783460697940688896
author Mizuno, Yu
Yamamotoya, Takeshi
Nakatsu, Yusuke
Ueda, Koji
Matsunaga, Yasuka
Inoue, Masa-Ki
Sakoda, Hideyuki
Fujishiro, Midori
Ono, Hiraku
Kikuchi, Takako
Takahashi, Masahiro
Morii, Kenichi
Sasaki, Kensuke
Masaki, Takao
Asano, Tomoichiro
Kushiyama, Akifumi
author_facet Mizuno, Yu
Yamamotoya, Takeshi
Nakatsu, Yusuke
Ueda, Koji
Matsunaga, Yasuka
Inoue, Masa-Ki
Sakoda, Hideyuki
Fujishiro, Midori
Ono, Hiraku
Kikuchi, Takako
Takahashi, Masahiro
Morii, Kenichi
Sasaki, Kensuke
Masaki, Takao
Asano, Tomoichiro
Kushiyama, Akifumi
author_sort Mizuno, Yu
collection PubMed
description Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.
format Online
Article
Text
id pubmed-6801943
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-68019432019-10-31 Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice Mizuno, Yu Yamamotoya, Takeshi Nakatsu, Yusuke Ueda, Koji Matsunaga, Yasuka Inoue, Masa-Ki Sakoda, Hideyuki Fujishiro, Midori Ono, Hiraku Kikuchi, Takako Takahashi, Masahiro Morii, Kenichi Sasaki, Kensuke Masaki, Takao Asano, Tomoichiro Kushiyama, Akifumi Int J Mol Sci Article Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration. MDPI 2019-09-21 /pmc/articles/PMC6801943/ /pubmed/31546603 http://dx.doi.org/10.3390/ijms20194680 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mizuno, Yu
Yamamotoya, Takeshi
Nakatsu, Yusuke
Ueda, Koji
Matsunaga, Yasuka
Inoue, Masa-Ki
Sakoda, Hideyuki
Fujishiro, Midori
Ono, Hiraku
Kikuchi, Takako
Takahashi, Masahiro
Morii, Kenichi
Sasaki, Kensuke
Masaki, Takao
Asano, Tomoichiro
Kushiyama, Akifumi
Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
title Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
title_full Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
title_fullStr Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
title_full_unstemmed Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
title_short Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
title_sort xanthine oxidase inhibitor febuxostat exerts an anti-inflammatory action and protects against diabetic nephropathy development in kk-ay obese diabetic mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801943/
https://www.ncbi.nlm.nih.gov/pubmed/31546603
http://dx.doi.org/10.3390/ijms20194680
work_keys_str_mv AT mizunoyu xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT yamamotoyatakeshi xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT nakatsuyusuke xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT uedakoji xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT matsunagayasuka xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT inouemasaki xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT sakodahideyuki xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT fujishiromidori xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT onohiraku xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT kikuchitakako xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT takahashimasahiro xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT moriikenichi xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT sasakikensuke xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT masakitakao xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT asanotomoichiro xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice
AT kushiyamaakifumi xanthineoxidaseinhibitorfebuxostatexertsanantiinflammatoryactionandprotectsagainstdiabeticnephropathydevelopmentinkkayobesediabeticmice